Is stress genetic?

Chris Smith asked geneticist, Patrick Short from the University of Cambridge, to get to the bottom of this question. 

Chris - That’s got quite strong genetic underpinnings, hasn’t it, your tendency towards mental illness?

Patrick - Yeah, absolutely. Things like obsessive compulsive disorder, schizophrenia, what I study; developmental disorders, all have very strong genetic underpinnings. They’re all different and, generally, the way they’ve been studied traditionally is looking at twins. You have monozygotic twins that have the exact same DNA and they’re raised by the same family, and then dizygotic twins, they share the same DNA their siblings would have, so half but also shared by the same family. If you look at, over time, the way monozygotic twins versus dizygotic twins get disorders like these mental health issues, you can actually work out how much of it is genetic in basis and how much has to do with other effects.

The way you handle stress is almost, in part, genetic. Also things like addiction; whether we’re susceptible to become addicted to alcohol or tobacco also have genetic underpinnings. So we’re beginning to understand this and figure out how to alter it a lot better these days now that we can genome sequence hundreds and thousands of people.

Chris - Does it work that you have a gene and that causes the condition, or does the gene in some way influence your behaviour that means you’re more susceptible to becoming depressed or getting schizophrenia? Do we understand how it works yet?

Patrick - We don’t fully understand how any of it works but I think both of those can be true. For instance, there are specific molecules that affect how you actually metabolise drugs like tobacco, or even pharmaceuticals that we take. You can have a slightly different protein that means the way you break down caffeine or tobacco is different.

But you can also have changes that affect your behaviour and affect the way you interact with the substance. This is commonly discussed in obesity for instance, because you can affect the way people metabolise the food physically, or you can affect their interaction with food and whether they’re likely to continue eating when they’re no longer hungry. So both of these things actually are at play.

Chris - Phillip?

Phillip - I was just going to say how do you disentangle experimentally how much of the influence, or how much of your susceptibility to these things is environmental and how much is genetic?

Patrick - The twin studies help in part because in one case they share half their DNA and in the other case they share all their DNA, but they have the same environmental influences. If something is fully genetic then you would see that the dizygotic twins that share half their DNA will have the shared trait together half the time, whereas the full twins will have it 100% of the time. If it’s only 25% genetic then you’ll see a different relationship basically.

And then there’s also a lot of experimental techniques that you can use to introduce changes and see how they affected to try and get at this causal link. Genetics is beautiful because it doesn’t have the reverse causality problem. You are born with your genome and you can’t change it in general. Although, as we talked about earlier, you may be able to change but, in general, you can’t change it. So it’s not that your behaviour is changing your DNA, it’s much more likely that your DNA is changing your behaviour.

Chris - What percentage difference in risk do the genes that you’re studying make to someone having depression, or schizophrenia, or obsessive compulsive disorder? What’s the loading or the contribution?

Patrick - The very rare and severe disorders that I study, it’s almost like night and day. If you have a mutation in the gene then you're almost 100% chance of getting this disorder and it’s going to be very severe, but I study very, very severe disorders. On the flip side, if you think about autism, or even schizophrenia, OCD, there are hundreds or thousands of independent, very small changes that actually just contribute a 2% risk or a 3% elevated risk over what we’d call the baseline. Most diseases are operating on this very complex genetic architecture.

Chris - The end point is becoming depressed or suffering OCD, but then there may be many different genes, thousands of genes that could, potentially, make a tiny contribution or tip the balance a little bit. So it’s not a given if you have this gene you’re going to get this condition, it’ll just increase your likelihood of going down that pathway?

Patrick - That’s exactly right.